Process for the preparation of pyrimidine derivatives

Abstract

The present invention relates to a new process for the preparation of a compound of formula (I), at technical scale, as well as novel intermediates thereof.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P39402 Process for the preparation of pyrimidine derivatives The present invention relates in particular to new processes for the preparation of a compound of formula (I) as well as to new intermediates thereof, both of which are useful for the synthesis of said compound at technical scale. Diabetes is a serious chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Complications of diabetes include, damage to the heart, blood vessels, eyes, kidneys, and nerves. Diabetes can increase risk of heart disease, and stroke. The results include serious effects on quality of life, health, and mortality. WHO Global Report on Diabetes, 2016, World Health Organization. The glucagon-like peptide-1 receptor (GLP-1 receptor, or GLP1R) has emerged as a potential target for treating type 2 diabetes. Its ligand, glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion, and increases insulin synthesis among many other effects. Doyle and Egan, 2007, Pharmacol. Ther. 113(3):546-593. GLP-1 is known to delay gastric emptying, suppress food intake, increase satiety, and reduce weight in humans. Shah and Vella, 2014 Rev Endocr Metab Disord.15(3): 181–187. Activating the GLP-1 receptor has been shown to have beneficial effects on insulin secretion and the maintenance of beta cell glucose sensing, transcription, synthesis, proliferation, and survival. Doyle and Egan, 2007, supra. While the GLP- 1 receptor is a promising therapeutic target, only a handful of GLP-1 receptor drugs have been approved to date, and most, or all of these are peptide, or polypeptide drugs. There is a need for additional therapies for treating metabolic diseases, and conditions, like type 2 diabetes. Small molecules targeting GLP-1 receptor should provide safe, stable, and easy to administer therapeutics for metabolic diseases, and conditions such as type 2 diabetes and / or obesity. 2-{[(2S,4S)-4-({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2- methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid, herein also termed compound of formula (I), has already been disclosed in WO2022165076 and WO2024026338. However, the routes described therein relied on several steps that were not considered ideal for large scale manufacturing due to moderate yields, the need for brute force chemistry and chromatography. The process presented herein presents improved regioselectivity in the formation of the pyrimidine and provides overall higher yields compared with the processes that were already known in the art. In summary, the present process presents a more convergent synthesis, fewer impurities in the final product, a higher yield and is in conclusion suitable for large scale manufacturing of 2-{[(2S,4S)-4-({2-[(2,4- Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylic acid as required in pharmaceutical production. In the route described in WO2024026338, the first step (step A,

[0700] ) of the synthesis – the coupling of the Boc-protected hydroxyl-piperidine derivate with 2,4-dichloropyrimidine provides moderate yields of between around 35-60%. The second step of the synthesis (step B,

[0702] ), namely the introduction of a methoxycarbonylation also provides only moderate yields of between around 35-65%. The third step (step C,

[0704] ) of that sequence, namely the reduction of the methyl ester with sodium borohydride also provides only moderate yields of around 65-75%. The overall yield of these three sequential steps (steps A-C) is thus only in the range of about 10- 30%. Together with the subsequent steps (steps D-F), the overall yield is in the range of well below 10%. The process of the present invention uses different building blocks and circumvents the previously mentioned sequence. As a result, the overall yield to obtain the final product is around 20% and thus significantly higher when compared with the processes known in the art. It was found that the objective of inventing a new process which is applicable on large scale could be reached with the improved processes of the present invention as described below. The invention thus relates in particular to a novel process with novel intermediates for the preparation of a compound of formula (I), wherein the process is safe, provides high yields and is generally suitable for a production on technical scale. The term "acceptable salt" refers to those salts of the compound as indicated, which retain the properties of the free bases, the free acids or the specifically disclosed salt form, which are not pharmaceutically or otherwise undesirable. In particular, it is to be understood that the term “acceptable salt” as used therein encompasses those salts that provide good crystallization, impurity rejection and / or are stable salts. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, , (- )-dibenzoy-L-tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, adipic acid, aspartic acid, pivalic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. The term “palladium catalyst” refers to any palladium catalyst that affects the rate and conversion of a chemical substrate compound to a product compound with a commercially acceptable yield and conversion. The palladium catalyzed reaction described here requires a zero valent palladium species (Pd(0)). Exemplary catalytically active Pd(0) species may be applied directly or may be formed in situ from a palladium source, in particular Pd(II), in combination with a ligand. In some embodiments or the invention, the palladium catalyst is either preformed or formed in situ. In some other aspects, the palladium catalyst is formed in situ with a suitable ligand such as described herein (e.g. L3 and L4). In some other aspects the palladium source is a preformed palladium catalyst. If one of the starting materials, intermediates or final products as described herein contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are for instance tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz). The compounds of formulas (vii), (viii) and (I-10) all comprise a “Boc” protective group as described above. The meaning of the “Boc” group is generally known to the person skilled in the art, but is nevertheless illustrated below exemplary in the compound of formula (vii): (vii) is an abbreviated representation While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. Specifically numbered aspects of the invention are: 1. A process comprising the reaction of a compound of formula (I-4) with a compound of formula (I-8) in presence of a suitable catalyst (cat-1), a suitable solvent and suitable base in order to arrive at a compound of formula (I-9) or an acceptable salt thereof wherein R is alkyl, benzyl or benzyl substituted with alkoxy and wherein X is a suitable leaving group such as for instance chloro, fluoro, bromo, iodo, O-tosylate, O-mesylate or O-nosylate, in particular wherein R is methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec- butyl, isobutyl, n-butyl, n-pentyl, tert-amyl, 2-ethylhexyl, phenyl, benzyl or p- methoxybenzyl and wherein X is chloro; in the above reaction the solvent can be solvent such as for instance toluene, THF, 2- MeTHF, MEK, MeCN, EtOAc, CPME, PhOMe, DMC, iPrOAc, gamma-valerolactone, cyrene, tAmOH, NBP or 1,4-dioxane; particular solvents for the above reaction are toluene, 2-MeTHF, DMC, EtOAc, iPrOAc, MEK or MeCN; in the above reaction the base can be a suitable organic or inorganic base, such as for instance phosphates or carbonates; particular bases for the above reaction are Cs2CO3, KOTMS, NaOtBu, DBU / NaTFA, K3PO4and K2CO3; in the above reaction the catalyst (cat-1) can be for instance a suitable palladium catalyst; particular catalysts (cat-1) are for instance selected from the group of: [Pd(allyl)Cl]2(CAS number 12012-95-2) plus ligand, [Pd(cinnayml)Cl]2 (CAS number 12131-44-1) plus ligand, Pd2(dba)3 (CAS number 51364-51-3) plus ligand, Pd(OAc)2(CAS numer 3375-31-3) plus ligand, [Pd(allyl)(Xantphos)]Cl (CAS number 879689-28-8), [PdCl2(Xantphos)] (CAS number 205319-10-4), [Pd(allyl)(tBuBrettPhos)]OTf (CAS number 1798782-15-6), [Pd(allyl)(DavePhos)]OTf, GPhos Pd G3 (CAS number 2489525-82-6), (rac)-BINAP Pd G3 (CAS number 2151915-22-7), tBuBrettPhos Pd G3 (CAS number 1536473-72-9), [Pd(allyl)(MorDalPhos)]OTf, [Pd(cinnamyl)(Me3(OMe)tBuXPhos)]OTf, CyJohnPhos Pd G3 (CAS number 2230788-64-2), [Pd(allyl)(EPhos)]OTf, EPhos Pd G4 (CAS number 2132978-44-8), [Pd(allyl)(Me4tBuXPhos)]OTf (CAS number 1798782-29-2), GPhos Pd G4, RockPhos Pd G3 (CAS number 2009020-38-4), Xantphos Pd G3 (CAS number 1445085-97-1), Xantphos Pd G4 (CAS number 1621274-19-8), [Pd(allyl)(RockPhos)] (CAS number 1798782-31-6), [Pd(allyl)Cl(EPhos)], [Pd(cinnamyl)(Josiphos SL-J002-1)]OTf, [Pd(allyl)Cl(CPhos)], [Pd(allyl)(cataXium PtB)]OTf, [Pd(allyl)(N-Xantphos)]Cl, [Pd(allyl)(Me3(OMe)tBuXPhos)]OTf, [Pd(allyl)(BippyPhos)]OTf (CAS number 1846558-62-0), [Pd(allyl)Cl(CyJohnPhos)], [Pd(allyl)(Cl)((R)-BINAP)] (CAS number 879689-47-1), Josiphos SL-J009-1 Pd G3, and MorDalPhos Pd G4 (CAS number 2230788-66-4), where applicable in presence of a suitable ligand such as for instance BINAP, Xantphos or Dppp, conveniently, the catalyst in the above reaction is [Pd(allyl)(Xantphos)]Cl or [Pd2(dba)3] / BINAP, the solvent is selected from 2-MeTHF, EtOAc, MeCN and PhMe and the base is selected from Cs2CO3, KOTMS, NaOtBu, DBU / NaTFA, K3PO4 and K2CO3; conveniently, the reaction is performed at between around 60 °C and around 120 °C, in particular between around 80 °C and around 100 °C; conveniently, the catalyst load is between around 0.01 mol% and around 5.0 mol%, more conveniently around 0.05 mol% and around 2.0 mol%, such as for instance at around 1%mol, and most conveniently around 0.1 mol%. The process according to aspect 1 further comprising the following preceding step: the reaction of a compound of formula (viii) or an acceptable salt thereof with a compound of formula (I-3) in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-4) wherein R is as defined in aspect 1; in the above reaction the solvent can be a polar solvent, such as for instance ACN, DCM, DMF, DMAC, DMSO, MEK, acetone, EtOAc, IPA, EtOH or MeOH and the base can be a suitable organic or inorganic base such as for instance DIPEA, TEA, sodium phosphate, disodium phosphate, monosodium phosphate, potassium phosphate, dipotassium phosphate, monopotassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, in particular the solvent is ACN and the base is K3PO4. The process according to aspect 1 further comprising the following preceding steps: (a) the reaction of a compound of formula (vii) in presence of a suitable solvent and a suitable acid to yield a compound of formula (viii) or an acceptable salt thereof (viii); and (b) the reaction of a compound of formula (vii) or an acceptable salt thereof with a compound of formula (I-3) in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-4) wherein R is as defined in aspect 1; in step (a) of the above reaction the solvent can be for instance DCM, 1,4-dioxane, water, MeOH or a mixture thereof and the acid can be for instance sulfuric acid, sulfonic acids, HCl or TFA, in particular the solvent is DCM and the acid is HCl; in step (b) of the above reaction the solvent can be a polar solvent, such as for instance acetonitrile, DMF, DMAC, DMSO, MEK, acetone, EtOAc, IPA, EtOH or MeOH and the base can be a suitable organic or inorganic base such as for instance DIPEA, TEA, sodium phosphate, disodium phosphate, monosodium phosphate, potassium phosphate, dipotassium phosphate, monopotassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, conveniently the solvent is acetonitrile and the base is potassium phosphate. The process according to aspect 2 or 3 further comprising the following preceding step: the reaction of a compound of formula (I-2) with a compound selected from , , in presence of a suitable solvent and a suitable acid in order to arrive at a compound of formula (I-3) wherein R is as defined in aspect 1; in the above reaction the solvent can be for instance THF, ACN, IPA, DCM or a mixture thereof, and the acid can be a suitable organic or inorganic acid such as for instance p- TsOH, conveniently, the solvent is THF and the acid is p-TsOH. The process according to aspect 4 further comprising the following preceding steps (a) and (b), or (a’) and (b’): (a) the reaction of a compound of formula (i) or a salt thereof with a compound of formula (ii) in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-1) (I-1); and (b) the reaction of a compound of formula (I-1) in presence of a suitable reducing agent and a suitable solvent to arrive at a compound of formula (I-2) (a’) the conversion of a compound of formula (iv) with a compound of formula (v) under suitable conditions to yield a compound of formula (vi) (b’) the reaction of a compound of formula (vi) with a suitable reducing agent and in presence of a suitable solvent to arrive at a compound of formula (I-2) wherein in the above process, Y is chloro or fluoro and R1 is alkyl, in particular Y is fluoro and R1 is methyl; and wherein R is as defined in aspect 1; suitable conditions for the reaction of step (a) include THF as solvent and potassium carbonate as base; suitable conditions for the reaction of step (b) include THF, MeOH, DCM, EtOAc or mixture thereof as solvent and Pd / C with H2 as reducing agent, in particular the solvent is THF and the reducing agent is Pd / C with H2 at a pressure of between 15 to 55 psi; suitable conditions for the reaction of step (a’) include the following conditions for the respective sub-steps: • sub-step (a’-1): compound of formula (iv) in presence of LiOH or NaOH, and in presence of IPA to yield • sub-step (a’-2): compound of formula (iv-a) in presence of DIPEA HCl and IPA to yield (iv-b); • sub-step (a’-3): compound of formula (iv-b) and compound of formula (v) in presence of T3P and EtOAc to yield a compound of formula (vi); suitable conditions for the reaction of step (b’) include the following conditions: the compound of formula (vi) in presence of LiBH4 in THF(2M), B(OEt)3 and DCM; or NaBH4, B(OEt)3 and DCM. The process according to aspect 4 further comprising the following preceding steps: (a) the reaction of a compound of formula (i) or an acceptable salt thereof in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-1) (I-1); and (b) the reaction of a compound of formula (I-1) (I-1) in presence of a suitable reducing agent and a suitable solvent to arrive at a compound of formula (I-2) wherein in the above process, Y is chloro or fluoro, in particular fluoro; and wherein R is as defined in aspect 1; suitable conditions for the reaction of step (a) include THF as solvent and potassium carbonate as base; suitable conditions for the reaction of step (b) include THF, MeOH, DCM, EtOAc or mixture thereof as solvent and Pd / C with H2 as reducing agent, in particular the solvent is THF and the reducing agent is Pd / C with H2 at a pressure of between 15 to 55 psi. The process according to aspect 4 further comprising the following preceding steps: (a’) the conversion of a compound of formula (iv) with a compound of formula (v) in presence of a suitable solvent and a suitable base or acid to yield a compound of formula (vi) (b’) the reaction of a compound of formula (vi) with a suitable reducing agent and in presence of a suitable solvent to arrive at a compound of formula (I-2) wherein in the above process, R1 is alkyl, in particular R1 is methyl; and wherein R is as defined in aspect 1; suitable conditions for the reaction of step (a’) include the following conditions for the respective sub-steps: • sub-step (a’-1): compound of formula (iv) in presence of LiOH or NaOH, and in presence of IPA to yieldor(iv-a); • sub-step (a’-2): compound of formula (iv-a) in presence of DIPEA HCl and IPA to yield (iv-b); • sub-step (a’-3): compound of formula (iv-b) and compound of formula (v) in presence of T3P and EtOAc to yield a compound of formula (vi); suitable conditions for the reaction of step (b’) include the following conditions: the compound of formula (vi) in presence of LiBH4 inTHF(2M), B(OEt)3 and DCM; or NaBH4, B(OEt)3 and DCM. A process comprising the reaction of a compound of formula (I-3) with a compound of formula (I-11) or a pharmaceutically acceptable salt of a compound of formula (I-11a) in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-9) or an acceptable salt thereof wherein R is alkyl, benzyl or benzyl substituted with alkoxy, in particular wherein R is methyl, n-pentyl, t-amyl, 2-ethylhexyl, benzyl or p-methoxybenzyl; suitable conditions for the above reaction are for instance 2-MeTHF as a solvent and potassium hydrogen carbonate as a base. The process according to any one of the preceding aspects further comprising the subsequent reaction of a compound of formula (I-9) or an acceptable salt thereof with one or more suitable deprotection reagents and in presence of a suitable solvent in order to arrive at a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R is as defined in aspect 1; suitable conditions for the above process include a suitable base or a suitable base as deprotection reagent in presence of a suitable solvent such as for instance toluene; other suitable conditions for the above process include Pd / C with H2in presence of a suitable solvent such as for instance MeOH. The process according to aspect 8 or 9 further comprising the precedent steps of: (a) the reaction of a compound of formula (I-8) with a compound of formula (vii) in presence of a suitable base and a suitable solvent and, optionally, a catalyst (cat-2) in order to arrive at a compound of formula (I-10) (I-10), and (b) the reaction of a compound of formula (I-10) (I-10) with a suitable acid and in presence of a suitable solvent to arrive at a compound of formula (I-11) L-(+)-tartrate(I-11); wherein R is as defined in aspect 8; suitable conditions for the reaction of step (a) are for instance a base selected from tBuOLi, tBuONa, tBuOK and KHMDS, and a solvent selected from THF, 2-MeTHF, NBP, DMI, ACN and dimethyl isosorbide, in particular wherein the base is tBuONa and the solvent is 2.MeTHF; conveniently, the reaction is performed at between around 20 °C and 90°C, in particular between around 30 °C and around 60°C, more particularly around 40 °C; alternatively, the reaction of step (a) can also be performed in presence of tBuOLi, Cs2CO3or K3PO4and a suitable solvent such as for instance toluene, 2-MeTHF, MeCN, EtOAc or 1,4-dioxane, as well as in presence of a suitable catalyst (cat-2) / ligand such as for instance CuI / 2,2-bipyridine, Ni(PPh3)4 / PPh3, Pd2(dba)3 / BINAP, Pd2(dba)3 / Dppp, GPhos Pd Pd G3, BINAP Pd G3, [Pd(allyl)(Xantphos)]Cl, MorDalphos Pd G3 or [Pd(allyl)DavePhos)]OTf; suitable conditions for the reaction of step (b) are for instance HCl as an acid and a mixture of TBME and water as solvent. A process according to any of aspects 2 to 7 or aspect 9 further comprising the following steps: (a) the compound of formula (I) is dissolved in a suitable solvent; e.g. MeOH, THF, butanone, 1-PrOH, acetone or a mixture thereof with any one of the mentioned solvents with water; (b) the mixture is filtered and the filter rinsed with a suitable solvent; (c) the solution is cooled down and / or suitable anti-sovent is added; the anti-solvent may be for instance water; (d) seeding crystals of the compound of formula (I) are added as powder or as suspension in a suitable solvent to the mixture; (e) the mixture is aged; (f) anti-solvent is added and the mixture cooled down; the anti-solvent may be for instance water; (g) the solids are filtered off and washed with a suitable solvent or solvent mixture; (h) the wet product is dried under reduced pressure. A process comprising the reaction of a compound of formula (I-7) (I-7) with a suitable chlorination agent in presence of a suitable solvent, and optionally a suitable base for quenching the reaction, in order to arrive at a compound of formula (I- 8’) suitable conditions for the above reaction are for instance conditions wherein the chlorination reagent is phosphorus oxychloride, the solvent is acetonitrile and the base is NaHCO3. A process comprising the reaction of a compound of formula (I-6) (I-6) with a compound of formula (xi) in presence of a suitable base and a suitable solvent in order to arrive at a compound of formula (I-7) a suitable solvent for the above reaction is for instance MeOH and a suitable base for the above reaction is for instance sodium methoxide. A process comprising the following steps: (a) the reaction of a compound of formula (I-5) (I-5) in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-6a) (I-6a); and (b) the subsequent reaction of the compound of formula (I-6a) with ammonium chloride to arrive at a compound of formula (I6) in the above reaction the solvent can be for instance MeOH and the base can be MeONa. A process comprising the reaction of a compound of formula (ix) with a compound of formula (x) (x) in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-5) suitable reactions for the above reaction are for instance wherein the solvent is a polar and aprotic solvent such as for instance THF, ACN, DMSO or DMF; and wherein the base is a suitable carbonate or hydroxide such as for instance cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide, conveniently the acid is ACN and the base is potassium carbonate. A process comprising the following reactions: (a) the reaction according to aspect 15; (b) the reaction according to aspect 14; (c) the reaction according to aspect 13; (d) the reaction according to aspect 12. A process according to any one of the preceding aspects, wherein the acceptable salt of a compound of formula (I-9) is a salt of formula (I-9b) The process according to any one of the preceding aspects, wherein R is alkyl, and wherein the deprotection reagent is selected from a suitable base, a suitable acid and H2+Pd / C; in particular the deprotection reagent is selected from DBU, TFA, KOH, LiOH, HCl, H2SO4, MsOH, H2+Pd / C and NaOH, more particular from KOH, LiOH, HCl, H2SO4, MsOH, H2+Pd / C and NaOH, and most particular the deprotection reagent is NaOH. A process according to any one of aspects 1 to 18, wherein R is methyl. A process according to any one of aspects 1 to 18, wherein R is benzyl. A process according to any one of aspects 1 to 18, wherein R is n-pentyl. A process according to any one of aspects 1 to 18, wherein R is t-amyl. A process according to any one of aspects 1 to 18, wherein R is 2-ethylhexyl. A process according to any one of aspects 1 to 18, wherein R is p-methoxybenzyl. The process according to any one of aspects 1 to 18, wherein R is benzyl or benzyl substituted with alkoxy and in particular methoxy, and wherein the deprotection reagents are Pd / C and H2. The process according to any one of the preceding aspects wherein the catalyst (cat-1) is Pd2(dba)3with a BINAP or Dppp ligand, and wherein the catalyst is used in presence of toluene or 1,4-dioxane as solvent, as well as in presence of cesium carbonate as base. The process according to any one of the preceding claims wherein the catalyst (cat-1) is GPhos Pd G3, and wherein the catalyst is used in presence of MEK, CAN, 2-MeTHF, DMC, PhMe, EtOAc or iPrOAc as solvent, as well as in presence of K3PO4 or K2CO3 as base. The process according to any one of the preceding claims wherein the catalyst (cat-1) is [Pd(allyl)(Xantphos)]Cl, and wherein the catalyst is used in presence of MEK, ACN, 2- MeTHF, DMC, PhMe, iPrOAc, BuOAc or EtOAc as solvent, as well as in presence of K3PO4 or K2CO3 as base. The process according to any one of the preceding claims wherein the catalyst (cat-1) is [Pd(allyl)(Xantphos)]Cl, and wherein the catalyst is used in presence of PhMe as solvent, as well as in presence of K3PO4 as base. The process according to any one of the preceding aspects, wherein the compound of formula (iii) is The process according to any one of the preceding aspects, wherein the compound of formula (I-9) is . The process according to any one of the preceding aspects, wherein the compound of formula (viii) is . The process according to any one of the preceding aspects, wherein the compound of formula (i) is . A compound of formula (I-6) A compound of formula (I-7) -6a’) (I-6a) (I-6a’).

[0002] . 38. A compound selected from

[0003] or an acceptable salt thereof. 39. A compound selected from

[0004] , , or an acceptable salt thereof. A compound of formula (I-9b) (I- A pharmaceutically acceptable salt of a compound of formula (I-9a) (I-9a), wherein R is methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec-butyl, isobutyl, n-butyl, n-pentyl, t-amyl, 2-ethylhexyl, benzyl or p-methoxybenzyl, in particular wherein R is methyl. A compound of formula (I-11) L-(+)-tartrate(I-11).

[0005] General schemes: Scheme 1 In the above scheme, Y is halogen and in particular fluoro. In the above scheme, R1 is alkyl. In the above scheme R is as described herein. In the above scheme, X is a suitable leaving group such as for instance halogen and in particular chloro. In step a, the solvent can be for instance THF or MeOH and the base can be for instance potassium carbonate or sodium carbonate. In step b, the solvent can be for instance THF, MeOH, DCM, EtOAc or a mixture thereof, in particular THF. The reaction of step b can be performed in presence of a suitable reducing agent such as for instance Pd / C and H2 at a pressure of between around 15 to 55 psi. In step c, the solvent can be for instance THF, ACN, IPA, DCM or a mixture thereof. The reaction of step c can be performed in presence of a suitable acid such as for instance p-TsOH. In step d, the solvent can be for instance DCM, 1,4-dioxane, water, MeOH or a mixture thereof. The reaction of step d can be performed in presence of a suitable acid such as for instance HCl or TFA. In step e, the solvent can be for instance acetonitrile, DMF, DMAc, DMSO, MEK, acetone, EtOAc, IPA, EtOH or MeOH. The reaction of step e can be performed in presence of a suitable base such as for instance DIPEA, TEA, sodium hydroxide, potassium hydroxide, sodium butoxide, potassium butoxide, sodium phosphate, disodium phosphate, monosodium phosphate, potassium phosphate, dipotassium phosphate, monopotassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. In step f, the solvent can be for instance toluene, THF or 1,4-dioxane. The reaction of step f can be performed in presence of a base such as for instance cesium carbonate. Alternatively, the reaction can also be performed in presence of a suitable Pd catalyst, a suitable solvent and a suitable base. For instance, the Pd catalyst can be [Pd2(dba)3] / BINAP or [Pd(allyl)(Xantphos)]Cl, the solvent can be for instance PhMe or EtOAc and the base can be for instance Cs2CO3, K2CO3or K3PO4. In step g, the solvent can be for instance toluene, 1,4-dioxane or MeOH. The reaction of step g can be performed in presence of a suitable base, acid or Pd / C with H2as appropriate. Suitable deprotecting reagents for the reaction of step g include DBU, TFA, KOH, LiOH, HCl, H2SO4, MsOH, H2+Pd / C and NaOH. The reaction of step a’ can for instance be performed under the following conditions: • sub-step (a’-1): compound of formula (iv) in presence of LiOH or NaOH, and in presence of IPA to yield (iv-a); • sub-step (a’-2): compound of formula (iv-a) in presence of DIPEA HCl and IPA to yield (iv-b); • sub-step (a’-3): compound of formula (iv-b) and compound of formula (v) in presence of T3P and EtOAc to yield a compound of formula (vi); The reaction of step b’ can for instance be performed under the following conditions: the compound of formula (vi) in presence of LiBH4in THF(2M), B(EtO)3and DCM; or NaBH4, B(OEt)3and DCM. In step e’, the solvent can be for instance 2-MeTHF. Conveniently, the reaction is performed in presence of a suitable base such as for instance potassium hydrogen carbonate. Scheme 2 In step a, the solvent can be for instance THF. Conveniently, the reaction is performed in presence of a suitable base such as for instance potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or cesium carbonate. In step b, the solvent can be for instance MeOH in presence of MeONa or EtOH in presence of EtONa. Next, ammonium chloride is added to provide I-6. In step c, the solvent can be for instance MeOH. Conveniently, the reaction is performed in presence of a suitable base such as for instance sodium methoxide. In step d, the solvent can be for instance acetonitrile. Conveniently, the reaction is performed in presence of a suitable chlorination reagent such as for instance phosphorus oxychloride and the reaction is quenched with a suitable base such as for instance NaHCO3. Scheme 3 In step a, the solvent can be for instance THF. Conveniently, the reaction is performed in presence of a suitable base such as for instance tBuOLi, tBuONa, tBuOK and KHMDS in a suitable solvent such as for instance THF, 2-MeTHF, NBP, DMI, ACN or dimethyl isosorbide. Conveniently, the reaction is performed between around 20 °C and around 90 °C, in particular between around 30 °C and around 60°C, more particularly around 40 °C. Alternatively, the reaction of step a can also be performed in presence of tBuOLi, Cs2CO3 or K3PO4 and a suitable solvent such as for instance toluene, 2-MeTHF, MeCN, EtOAc or 1,4- dioxane, as well as in presence of a suitable catalyst / ligand such as for instance CuI / 2,2- bipyridine, Ni(PPh3)4 / PPh3, Pd2(dba)3 / BINAP, Pd2(dba)3 / Dppp, GPhos Pd Pd G3, BINAP Pd G3, [Pd(allyl)(Xantphos)]Cl, MorDalphos Pd G3 or [Pd(allyl)DavePhos)]OTf. In step b, the solvent can be for instance a mixture of TBME and water. Conveniently, the reaction is performed in presence of a suitable acid such as for instance HCl. Experimental Part The following experiments are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. The individual steps may be combined, modified and the sequence altered in order to yield the compound of formula (I) or an intermediate thereof, however the scope of the invention is not limited by the reactions specifically described in the examples but is to be construed in view of the whole disclosure of the present invention including inter alia also the general schemes and common general knowledge. Abbreviations: ACN = acetonitrile; BINAP = [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]; CAS = chemical abstract service; dba = disbenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMAc = N,N- dimethylacetamide; DMF = dimethylformamide; DMSO dimethyl sulfoxide; Dppp = 1,3- Bis(diphenylphosphino)propane; EtOAc = ethyl acetate; EtOH = ethanol; IPA = 2-propanol; iPrOAc = isopropyl acetate; MCH = methylcyclohexane; MeCN = acetonitrile; MeOH = methanol; MEK = methyl ethyl ketone; MS = mass spectrometry; MsCl = mesyl chloride; MsOH = methanesulfonic acid; NEt3 = triethyl amine; p-TsOH = para-toluenesulfonic acid; TBAOH = tetrabutylammonium hydroxide; TBME = tert-butyl methyl ether; TEA = triethylamine; THF = tetrahydrofuran. Intermediate 1 - Methyl 4-nitro-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate A mixture of methyl 3-fluoro-4-nitrobenzoate (8.10 kg, 1.00 eq.; CAS number 185629-31-6), 4- methylbenzene-1-sulfonic acid;1-[(2S)-oxetan-2-yl]methanamine (1 / 1) (12.65 kg, 1.05 eq.; CAS number 2740593-38-6), potassium carbonate (14.1 kg, 2.50 eq.) and THF (74.5kg) was stirred for 16 hours at 60 °C. The solids were filtered off and washed with THF (20.5 kg). The THF solution of methyl 4-nitro-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate was used in the subsequent step. Intermediate 1’ - Benzyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate A mixture of 3-fluoro-4-nitro-benzoic acid (20 g, 1.00 eq.), SO2Cl2(152 g, 11.8 eq.), and toluene (200 mL) was stirred for 6 hours at 90 °C. The reaction mixture was concentrated to dryness under reduced pressure. MeCN (200 mL) was added into the solution. NaHCO3 (13.1 g, 1.44 eq.) and phenylmethanol (11.7 g, 1.00 eq.) were added and the mixture was stirred for 6 hours at 25 °C. The solids were filtered off and washed with DCM (200 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (EtOAc / PE=1 v / 10 v).11.7 g of benzyl 3-fluoro-4-nitro-benzoate were obtained. A mixture of benzyl 3-fluoro-4-nitro-benzoate (11.7 g, 1.00 eq.), 4-methylbenzene-1-sulfonic acid;1-[(2S)- oxetan-2-yl]methanamine (1 / 1) (11.6 g, 1.05 eq.; CAS number 2740593-38-6), potassium carbonate (15.3 g, 2.60 eq.) and THF (120 mL) was stirred for 4 hours at 60 °C. The solids were filtered off through diatomite (6 g) and washed with THF (72 mL). The THF solution of benzyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate was used in the subsequent step. Intermediate 1’’ - Pentyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (not isolated) A mixture of 3-fluoro-4-nitro-benzoic acid (20 g, 1.00 eq.), SO2Cl2 (152 g, 11.8 eq.), and toluene (200 mL) was stirred for 6 hours at 90 °C. The reaction mixture was concentrated to dryness under reduced pressure. MeCN (200 mL) was added into the solution. NaHCO3(13.1 g, 1.44 eq.) and 1-Pentanol (9.5 g, 1.00 eq.) were added and the mixture was stirred for 6 hours at 25 °C. The solids were filtered off and washed with DCM (200 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (EtOAc / PE=1 v / 10 v).9.0 g of pentyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate were obtained. A mixture pentyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (9.0 g, 1.00 eq.), 4-methylbenzene-1-sulfonic acid;1-[(2S)-oxetan-2-yl]methanamine (1 / 1) (11.6 g, 1.05 eq.; CAS number 2740593-38-6), potassium carbonate (12.6 g, 2.59 eq.) and THF (90 mL) was stirred for 4 hours at 60 °C. The solids were filtered off through diatomite (4.5 g) and washed with THF (54 mL). The THF solution of pentyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate was used in the subsequent step. Intermediate 1’’’ - 2-Ethylhexyl 4-nitro-3-[[(2~{S})-oxetan-2-yl]methylamino]benzoate (not isolated) A mixture of 3-fluoro-4-nitro-benzoic acid (20 g, 1.00 eq.), SO2Cl2 (152 g, 11.8 eq.), and toluene (200 mL) was stirred for 6 hours at 90 °C. The reaction mixture was concentrated to dryness under reduced pressure. MeCN (200 mL) was added into the solution. NaHCO3 (13.1 g, 1.44 eq.) and 2-ethylhexan-1-ol (14.1 g, 1.00 eq.) were added and the mixture was stirred for 6 hours at 25 °C. The solids were filtered off and washed with DCM (200 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (EtOAc / PE=1 v / 10 v).17.7 g of 2-ethylhexyl 4-nitro-3-[[(2S)-oxetan-2- yl]methylamino]benzoate were obtained. A mixture 2-ethylhexyl 4-nitro-3-[[(2S)-oxetan-2- yl]methylamino]benzoate (17.7 g, 1.00 eq.), 4-methylbenzene-1-sulfonic acid;1-[(2S)-oxetan-2- yl]methanamine (1 / 1) (16.2g, 1.05 eq.; CAS number 2740593-38-6), potassium carbonate (21.4 g, 2.59 eq.) and THF (200 mL) was stirred for 4 hours at 60 °C. The solids were filtered off through diatomite (9.0 g) and washed with THF (108 mL). The THF solution of 2-ethylhexyl 4- nitro-3-[[(2~{S})-oxetan-2-yl]methylamino]benzoate was used in the subsequent step. Intermediate 1’’’’ - (4-Methoxyphenyl)methyl 4-nitro-3-[[(2S)-oxetan-2- yl]methylamino]benzoate A mixture of 3-fluoro-4-nitro-benzoic acid (20 g, 1.00 eq.), SO2Cl2(152 g, 11.8 eq.), and toluene (200 mL) was stirred for 6 hours at 90 °C. The reaction mixture was concentrated to dryness under reduced pressure. MeCN (200 mL) was added into the solution. NaHCO3(13.1 g, 1.44 eq.) and 1-Pent (9.5 g, 1.00 eq.) were added and the mixture was stirred for 6 hours at 25 °C. The solids were filtered off and washed with DCM (200 mL). The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (EtOAc / PE=1 v / 10 v).21.3 g of benzyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate were obtained. A mixture (4-methoxyphenyl)methyl 4-nitro-3-[[(2S)-oxetan-2- yl]methylamino]benzoate (21.3 g, 1.00 eq.), 4-methylbenzene-1-sulfonic acid;1-[(2S)-oxetan-2- yl]methanamine (1 / 1) (18.9 g, 1.05 eq.; CAS number 2740593-38-6), potassium carbonate (25 g, 2.59 eq.) and THF (200 mL) was stirred for 4 hours at 60 °C. The solids were filtered off through diatomite (10.5 g) and washed with THF (126 mL). The THF solution of (4- methoxyphenyl)methyl 4-nitro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate was used in the subsequent step. Intermediate 2 - Methyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate Palladium on activated carbon (1.35 kg) was added to the THF solution of methyl 4-nitro-3- ({[(2S)-oxetan-2-yl]methyl}amino)benzoate (Intermediate 1). The reaction mixture was stirred under hydrogen pressure at 45 psi and 40 °C for 16 hours. The reaction mixture was cooled down to 25 °C. The solids were filtered off and washed with THF (16.5 kg). The THF solution of methyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate was used in the subsequent step. Intermediate 2‘ - Benzyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (not isolated) Palladium on activated carbon (1.8 g) was added to the THF solution of benzyl 4-nitro-3-[[(2S)- oxetan-2-yl]methylamino]benzoate (intermediate 1’). The reaction mixture was stirred under hydrogen pressure at 45 psi and 45 °C for 21 hours. The solids were filtered off and washed with THF (50 mL). The THF solution of benzyl 4-amino-3-({[(2S)-oxetan-2- yl]methyl}amino)benzoate was used in the subsequent step. Intermediate 2’‘ - Pentyl 4-amino-3-[[(2~{S})-oxetan-2-yl]methylamino]benzoate (not isolated) Palladium on activated carbon (1.4 g) was added to the THF solution of benzyl 4-nitro-3-[[(2S)- oxetan-2-yl]methylamino]benzoate (intermediate 1’’). The reaction mixture was stirred under hydrogen pressure at 45 psi and 45 °C for 21 hours. The solids were filtered off and washed with THF (50 mL). The THF solution of pentyl 4-amino-3-({[(2S)-oxetan-2- yl]methyl}amino)benzoate was used in the subsequent step. Intermediate 3 - Methyl 2-(chloromethyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole- 6-carboxylate The THF solution of methyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (Intermediate 2) was concentrated to 3-4 v / w under reduced pressure. THF (51.5 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. THF (51.5 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. THF (47.5 kg), 1,1,1- trimethoxy-2-chloroethane (6.9 kg, 1.00 eq.), and p-toluenesulfonic acid monohydrate (0.3 kg, 0.05 eq.) were added. THF (24 kg) was added and the reaction mixture was stirred for 2 hours at 60 °C. The reaction mixture was concentrated to 3-4 v / w under reduced pressure. EtOAc (50 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. EtOAc (50 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. EtOAc (90 kg) was added. The mixture was cooled down to 30 °C and washed with water twice (2 x 45 kg). The organic layer was concentrated to 3-4 v / w under reduced pressure. TBME (51 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. TBME (46 kg) and EtOAc (30 kg) were added and the mixture was concentrated to 3-4 v / w under reduced pressure. TBME (41 kg) was added and the mixture was concentrated to 3-4 v / w under reduced pressure. n- Heptane / TBME (5 / 1, 78 kg) was added to the mixture at 45 °C over 2 hours. The mixture was stirred at 45 °C for 2 hours, cooled down to 0 °C over 3.5 hours and stirred at 10 °C for 6 hours. The solids were filtered off and washed with n-heptane (25kg). The wet product was dried at 45 °C under reduced pressure.7.2kg methyl 2-(chloromethyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H- benzimidazole-6-carboxylate were obtained. Intermediate 3’ - Benzyl 2-(chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5- carboxylate The THF solution of methyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (intermediate 2’) was concentrated to dryness under reduced pressure. THF (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. THF (100 mL), p- toluenesulfonic acid monohydrate (0.81 g, 0.10 eq.) and 1,1,1-trimethoxy-2-chloroethane (9.2 g, 1.40 eq.) were added. The reaction mixture was stirred for 2 hours at 60 °C. The reaction mixture was concentrated to dryness under reduced pressure. EtOAc (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. EtOAc (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. EtOAc (350 mL) was added and filter the mixture through diatomite (12 g). Wash the organic layer with 7 w% NaHCO3(100 mL). Wash the organic layer with process water (100 mL). Wash the organic layer with process water (100 mL). The organic was concentrated under reduced pressure to give a residue. The residual was purified by column chromatography (EtOAc / PE = 1 v / 1 v).9.1 g of benzyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 3’’ – Pentyl 2-(chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5- carboxylate The THF solution of pentyl 4-amino-3-({[(2S)-oxetan-2-yl]methyl}amino)benzoate (intermediate 2’’) was concentrated to dryness under reduced pressure. THF (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. THF (100 mL), p- toluenesulfonic acid monohydrate (0.67 g, 0.10 eq.) and 1,1,1-trimethoxy-2-chloroethane (7.6 g, 1.40 eq.) were added. The reaction mixture was stirred for 2 hours at 60 °C. The reaction mixture was concentrated to dryness under reduced pressure. EtOAc (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. EtOAc (200 mL) was added and the mixture was concentrated to dryness under reduced pressure. EtOAc (350 mL) was added and filter the mixture through diatomite (9 g). Wash the organic layer with 7 w% NaHCO3(100 mL). Wash the organic layer with process water (100 mL). Wash the organic layer with process water (100 mL). The organic was concentrated under reduced pressure to give a residue. The residual was purified by column chromatography (EtOAc / PE = 1 v / 1 v).7.1 g of pentyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 4 - Methyl 2-{[(2S,4S)-4-hydroxy-2-methylpiperidin-1-yl]methyl}-1-{[(2S)- oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylate A mixture of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (52.25 g, 1.1 eq.; CAS 790667-99-1), DCM (260 mL) and 4M HCl (460 mL, 11 eq.) was stirred for 2 hours at 25 °C. The reaction mixture was concentrated to 3 v / w under reduced pressure. MeCN (500 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. MeCN (500 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. MeCN (350 mL) was added and the mixture was cooled down to 25 °C. Methyl 2-(chloromethyl)-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylate (65.5 g, 1.0 eq., intermediate 3) and potassium phosphate (133.7 g, 2.5 eq.) were added and the mixture was stirred for 20 hours at 80 °C. The solids were filtered off and washed with DCM (260 mL). The solution was concentrated to 3 v / w under reduced pressure. TBME (650 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. TBME (650 mL) and the mixture was concentrated to 3 v / w under reduced pressure. TBME (650 mL) was added and the mixture was stirred at 45 °C for 2 hours, cooled down to 0 °C over 4.5 hours and stirred at 0 °C for 2 hours. The solids were filtered off and washed with TBME (130 mL). The wet product was dried at 45 °C under reduced pressure. 66.57 g methyl 2-{[(2S,4S)-4-hydroxy-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2- yl]methyl}-1H-benzimidazole-6-carboxylate were obtained. Intermediate 4’ - Benzyl 2-[[(2S,4~S)-4-hydroxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate A mixture of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (330 mg, 1.1 eq.; CAS 790667-99-1), 4M HCl in MeOH solution (1.9 mL, 4.54 eq.) was stirred for 18 hours at 25 °C. The reaction mixture was concentrated to 3 v under reduced pressure. MeOH (1.5 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (3.3 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. MeCN (3.3 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (3.3 mL) was added into the solution. Potassium phosphate (572 mg, 2.00 eq.), MeCN (2.5 mL) and benzyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (0.5 g, 1.00 eq., intermediate 3’) were added and the mixture was stirred for 16 hours at 70 °C. Adjusted solution to 35 °C and added THF (5 mL) into the mixture. The solids were filtered off and washed with THF (10 mL). A mixture of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (4.2 g, 1.25 eq.), 4M HCl in MeOH solution (23.7 mL, 3.99 eq.) was stirred for 16 hours at 25 °C. The reaction mixture was concentrated to 3 v under reduced pressure. MeOH (20 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (20 mL) was added and the mixture was concentrated to 3 v under reduced pressure (3 times repeated), then the mixture was cooled down to 25 °C. Potassium phosphate (6.5 g, 2.02eq.), MeCN (25 mL) and benzyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (5.6g, 1.00 eq., intermediae 3’) were added and the mixture was stirred for 16 hours at 70 °C. Adjusted solution to 35 °C and added THF (25 mL) into the mixture. The solids were filtered off and washed with THF (110 mL). The two reactions above were combined for work up. The solution was concentrated to 3 v under reduced pressure. Toluene (36 mL) was added and the mixture was concentrated to 3 vunder reduced pressure. Toluene (36 mL) and the mixture was concentrated to 3 v under reduced pressure. Toluene (36 mL) was added the mixture was concentrated to 3 v under reduced pressure. Toluene(61 mL) was added and the mixture was stirred at 45 °C for 3 hours, cooled down to 20 °C over 4 hours and stirred at 20 °C for 12 hours. The solids were filtered off and washed with toluene (12 mL) and water (12 mL). The wet cake slurried with MeCN / H2O (1.8 mL / 16 mL). Then the solids were filtered and washed with MeCN / H2O (12 mL, 1 v / 9 v) and dried at 45 °C under reduced pressure.4.5g of benzyl 2-[[(2S,4~S)-4-hydroxy-2-methyl-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 4’’ – Pentyl 2-[[(2S,4~S)-4-hydroxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate A mixture of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (351 mg, 1.1 eq.; CAS 790667-99-1), 4M HCl in MeOH solution (2.0 mL, 4.55 eq.) was stirred for 18 hours at 25 °C. The reaction mixture was concentrated to 3 v under reduced pressure. MeOH (1.5 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (3.3 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. MeCN (3.3 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (3.3 mL) was added into the solution. Potassium phosphate (572 mg, 2.00 eq.), MeCN (2.5 mL) and pentyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (0.5 g, 1.00 eq., intermediate 3’) were added and the mixture was stirred for 16 hours at 70 °C. Adjusted solution to 35 °C and added THF (5 mL) into the mixture. The solids were filtered off and washed with THF (10 mL). A mixture of tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (4.2 g, 1.25 eq.), 4M HCl in MeOH solution (23.7 mL, 3.99 eq.) was stirred for 16 hours at 25 °C. The reaction mixture was concentrated to 3 v under reduced pressure. MeOH (20 mL) was added and the mixture was concentrated to 3 v under reduced pressure. MeCN (20 mL) was added and the mixture was concentrated to 3 v under reduced pressure (3 times repeated), then the mixture was cooled down to 25 °C. Potassium phosphate (5.9 g, 2.00 eq.), MeCN (25 mL) and pentyl 2- (chloromethyl)-3-[[(2~{S})-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (4.9 g, 1.00 eq., intermediate 3’) were added and the mixture was stirred for 16 hours at 70 °C. Adjusted solution to 35 °C and added THF (25 mL) into the mixture. The solids were filtered off and washed with THF (100 mL). The two reactions above were combined for work up. The solution was concentrated to 3 v under reduced pressure. Toluene (36 mL) was added and the mixture was concentrated to 3 v under reduced pressure. Toluene (36 mL) and the mixture was concentrated to 3 v under reduced pressure. Toluene (36 mL) was added the mixture was concentrated to 3 v under reduced pressure. Toluene(61 mL) was added and the mixture was stirred at 45 °C for 3 hours, cooled down to 20 °C over 4 hours and stirred at 20 °C for 12 hours. The solids were filtered off and washed with toluene (12 mL) and water (12 mL). The wet cake slurried with MeCN / H2O (1.8 mL / 16 mL). Then the solids were filtered and washed with MeCN / H2O (12 mL, 1 v / 9 v) and dried at 45 °C under reduced pressure.4.9 g of pentyl 2-[[(2S,4~S)-4-hydroxy-2-methyl-1- piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 5 - (2,4-Difluorophenoxy)acetonitrile Chloroacetonitrile (140 g, 1.20 eq.; CAS number 107-14-2) was slowly added to a mixture of cesium carbonate (1004 g, 2.0 eq.) and 2,4-difluorophenol (200 g, 1.0 eq.; CAS number 367-27- 1) in THF (1780 g). The mixture was stirred for 20 hours at 30 °C. The solids were filtered off and washed with THF (1780 g). The THF solution of (2,4-difluorophenoxy)acetonitrile was used in the subsequent step. Intermediate 6 - 2-(2,4-Difluorophenoxy)acetamidine;hydrochloride The THF solution of (2,4-difluorophenoxy)acetonitrile (Intermediate 5) was concentrated to 2 v / w under reduced pressure. Methanol (7.9 w / w) was added and the mixture was concentrated to 2 v / w under reduced pressure. Methanol (7.9 w / w) was added and the mixture was concentrated to 2 v / w under reduced pressure. Methanol (5.5 w / w) was added. Sodium methoxide (solution in methanol, 1.0 eq.) was added and the mixture was stirred for 20 hours at 20 °C. Ammonium chloride (4.0 eq.) was added and the mixture was stirred for 6 hours at 25 °C. The solids were filtered off and washed with methanol (2.4 w / w). The methanol solution of 2-(2,4- difluorophenoxy)acetamidine;hydrochloride was used in the subsequent step. Intermediate 7 - 2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-ol Methanol (6.0 w / w), ethyl (2E)-3-hydroxyprop-2-enoate;sodium (1 / 1 molar ratio) (0.82 eq.; CAS number 863581-67-3) and sodium methoxide (solution in methanol, 1.0 eq.) were added to the methanol solution of 2-(2,4-difluorophenoxy)acetamidine;hydrochloride (Intermediate 6). The mixture was stirred at 20 °C. Additional portions of ethyl (2E)-3-hydroxyprop-2-enoate;sodium (1 / 1) were added (0.14 eq., 0.10 eq. and 0.14 eq.) to reach reaction completion. The reaction mixture was concentrated to 3V under reduced pressure.1N HCl was added at 25 °C over 1 hour to adjust to pH 5.5. The solids were filtered off and washed with washed with water (3 w / w). The wet cake, water (5 w / w) and methanol (1 w / w) were mixed. The mixture was stirred at 45 °C for 2 hours, cooled down to 25 °C over 2 hours and stirred at 25 °C for 8 hours. The solids were filtered off and washed with water (2.0 w / w). The wet cake was mixed with TBME (3.7 w / w). The mixture was stirred at 45°C for 8 hours, cooled down to 0 °C over 5 hours and stirred at 0 °C for 6 hours. The solids were filtered off and washed with TBME (1.1 w / w). The wet product was dried at 45 °C under reduced pressure.207.7 g 2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-ol were obtained. Intermediate 8 - 4-Chloro-2-[(2,4-difluorophenoxy)methyl]pyrimidine Phosphorus oxychloride (2.00 eq.) was added to a mixture of 2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-ol (1.00 eq., 157 g; Intermediate 7) and ACN (7.9 w / w). The mixture was stirred at 80 °C for 20 hours. The mixture was cooled down to 25 °C. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate (15 w / w) at 25 °C over 2 hours, and the mixture was stirred at 25 °C for 4 hours. The mixture was concentrated under reduced pressure and the mixture was cooled down to 25 °C. TBME (11 w / w) was added and the mixture was stirred for 1 hour at 25 °C. The solids were filtered off and washed with TBME (1.5 w / w). The organic layer was separated and filtered through CUNO filter, washing with TBME (3.7 w / w). The solution was concentrated to 3 v / w under reduced pressure. MCH (7.7 w / w) was added and the solution was concentrated to 3 v / w under reduced pressure. MCH (7.7 w / w) was added and the solution was concentrated to 3 v / w under reduced pressure. MCH (1.6 w / w) was added and the mixture was stirred at 45 °C for 2 hours, cooled down to -10 °C over 5.5 hours and stirred at -10 °C for 4 hours. The solids were filtered off and washed with MCH (2.3 w / w). The wet product was dried at 50 °C under reduced pressure.139 g 4-chloro-2- [(2,4-difluorophenoxy)methyl]pyrimidine were obtained. Intermediate 9 - (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;methyl 2-{[(2S,4S)-4-({2- [(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)- oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylate A mixture of Pd2(dba)3(1.18 g, 0.01 eq.), (R)-BINAP (1.61 g, 0.02 eq.), toluene(500 mL), 4- chloro-2-[(2,4-difluorophenoxy)methyl]pyrimidine (37.64 g, 1.1 eq.; Intermediate 8), methyl 2- {[(2S,4S)-4-hydroxy-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H- benzimidazole-6-carboxylate (50 g, 1.0 eq.; Intermediate 4) and cesium carbonate (84.28 g, 2.0 eq.) was stirred for 12 hours at 100 °C. The reaction mixture was cooled down and filtered. N- acetyl cysteine (23 g) was added and the mixture was stirred for 12 hours at 50 °C and 12 hours at 25 °C. The solids were filtered off and washed with toluene (150 mL). The filtrate was concentrated 2 v / w under reduced pressure. TBME (385 mL) was added and the mixture was concentrated to 2 v / w under reduced pressure. TBME (385 mL) was added and the mixture was concentrated to 2 v / w under reduced pressure. TBME (300 mL) was added. (2R,3R)-2,3- bis(benzoyloxy)butanedioic acid;methyl 2-{[(2S,4S)-4-({2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylate seeding crystals (0.1 g) and a solution of (-)- dibenzoy-L-tartaric acid ((L)-DBTA) in 2-MeTHF (35 g pre-seeding and 70 g post-seeding) were added at 50 °C. The mixture was stirred at 50 °C for 5 hours, cooled down to 0 °C over 5 hours and stirred at 0 °C for 8 hours. The solids were filtered off and washed with TBME / 2-MeTHF (3 / 1; 210 mL). The wet product was dried at 45 °C under reduced pressure.131 g (2R,3R)-2,3- bis(benzoyloxy)butanedioic acid;methyl 2-{[(2S,4S)-4-({2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylate were obtained. Intermediate 9, alternative route - (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;methyl 2- {[(2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylate A mixture of (2S,3S)-2,3-dihydroxybutanedioic acid;2-[(2,4-difluorophenoxy)methyl]-4- {[(2S,4S)-2-methylpiperidin-4-yl]oxy}pyrimidine (1 / 1) (76.88 g, 1.00 eq.; Intermediate 11), aqueous sodium hydroxide (6.1 w / w, 2.0M) and 2-MeTHF (4.7 w / w) was stirred for 1 hour at 25 °C. The aqueous layer was separated. Methyl 2-(chloromethyl)-1-{[(2S)-oxetan-2-yl]methyl}- 1H-benzimidazole-6-carboxylate (1.00 eq.; Intermediate 3), potassium hydrogen carbonate (3.0 eq.) and 2-MeTHF (1.0 w / w) were added and the mixture was stirred for 18 hours at 85 °C. The reaction mixture was cooled down to 25°C and washed with water (3.1 w / w). The organic layer was concentrated to 2-3 v / w under reduced pressure. TBME (2.4 w / w) was added and the mixture was concentrated to 2-3 v / w under reduced pressure. TBME (2.4 w / w) was added and the mixture was concentrated to 2-3 v / w under reduced pressure. TBME (0.6 w / w), (2R,3R)-2,3- bis(benzoyloxy)butanedioic acid;methyl 2-{[(2S,4S)-4-({2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylate seeding crystals (0.01 w / w) and a 2-MeTHF solution of (-)-dibenzoy-L-tartaric acid (0.4 w / w pre-seeding and 0.8 w / w post-seeding) were added at 50°C. The mixture was stirred at 50 °C for 2 hours. TBME (1.2 w / w) was added and the slurry was cooled down to 0 °C over 5 hours and stirred at 0 °C for 8 hours. The solids were filtered off and washed with TBME / 2-MeTHF (3 / 1, 0.6 w / w). The wet product was dried at 40 °C under reduced pressure.147.4 g (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;methyl 2- {[(2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylate were obtained. Intermediate 9’ - (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;benzyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan- 2-yl]methyl]benzimidazole-5-carboxylate A mixture of Pd2(dba)3(10 mg, 0.01 eq.), BINAP (14 mg, 0.02 eq.), toluene (5.3 mL), 4-chloro- 2-[(2,4-difluorophenoxy)methyl]pyrimidine (327 mg, 1.11 eq., intermediate 8), benzyl 2- [[(2S,4~S)-4-hydroxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (0.5 g, 1.00 eq., intermediate 4’) and cesium carbonate (725 mg, 2.00 eq.) was stirred for 16 hours at 100 °C. A mixture of Pd2(dba)3 (82 mg, 0.01 eq.), BINAP (111 mg, 0.02 eq.), toluene (42 mL), 4-chloro- 2-[(2,4-difluorophenoxy)methyl]pyrimidine (2.6 g, 1.11 eq.), benzyl 2-[[(2S,4~S)-4-hydroxy-2- methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (4.0 g, 1.00 eq.) and cesium carbonate (5.8 g, 2.00 eq.) was stirred for 16 hours at 100 °C. Two reactions above were combined for work up. The solids were filtered off and rinsed with toluene (10.3 mL). N-acetyl cysteine (1.9 g, 1.16 eq.) was added and the mixture was stirred for 8 hours at 50 °C. The solids were filtered off and washed with toluene (10 mL). The solution was concentrated to 6 v under reduced pressure. A solution of (-)-dibenzoy-L-tartaric acid (4.5 g, 1.25 eq.) in 2-MeTHF (22.5 mL) were added into the mixture at 45 °C. The mixture stirred at 45 °C for 2 hours. The mixture was concentrated to dryness.11.7 g of crude (2R,3R)-2,3- bis(benzoyloxy)butanedioic acid;benzyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 9’’ - (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;pentyl 2-[[(2S,4S)-4-[2- [(2,4-difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)- oxetan-2-yl]methyl]benzimidazole-5-carboxylate A mixture of Pd2(dba)3(11 mg, 0.01 eq.), BINAP (15 mg, 0.02 eq.), toluene (5.3 mL), 4-chloro- 2-[(2,4-difluorophenoxy)methyl]pyrimidine (338 mg, 1.11 eq., intermediate 8), pentyl 2- [[(2S,4~S)-4-hydroxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (0.5 g, 1.00 eq., intermediate 4’’) and cesium carbonate (759 mg, 2.00 eq.) was stirred for 16 hours at 100 °C. A mixture of Pd2(dba)3 (94 mg, 0.01 eq.), BINAP (128 mg, 0.02 eq.), toluene (46 mL), 4-chloro- 2-[(2,4-difluorophenoxy)methyl]pyrimidine (3.0 g, 1.11 eq.), pentyl 2-[[(2S,4~S)-4-hydroxy-2- methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (4.4 g, 1.00 eq.) and cesium carbonate (6.7 g, 2.00 eq.) was stirred for 16 hours at 100 °C. Two reactions above were combined for work up. The solids were filtered off and rinsed with toluene (11.3 mL). N-acetyl cysteine (2.1 g, 1.16 eq.) was added and the mixture was stirred for 8 hours at 50 °C. The solids were filtered off and washed with toluene (11.2 mL). The solution was concentrated to 6 v under reduced pressure. A solution of (-)-dibenzoy-L-tartaric acid (5.1 g, 1.25 eq.) in 2-MeTHF (24.6 mL) were added into the mixture at 45 °C. The mixture stirred at 45 °C for 2 hours. The mixture was concentrated to dryness.11.7 g of crude (2R,3R)-2,3- bis(benzoyloxy)butanedioic acid;pentyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate were obtained. Intermediate 10 - Tert-butyl (2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4- yl}oxy)-2-methylpiperidine-1-carboxylate A mixture of 4-chloro-2-[(2,4-difluorophenoxy)methyl]pyrimidine (50.0 g, 1.00 eq.; Intermediate 8), tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (48.3 g, 1.10 eq.; CAS 790667-99-1), lithium tert-butoxide (15.5 g, 1.00 eq.) and THF (445 g) was stirred for 7 hours at 65 °C. Lithium tert-butoxide (15.5 g, 1.00 eq.) was added and the mixture was stirred for 16 hours at 65 °C. Lithium tert-butoxide (15.5 g, 1.00 eq.) was added and the mixture was stirred for 12 hours at 65 °C. The reaction mixture was cooled down to 25 °C. The THF solution of tert-butyl (2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2- methylpiperidine-1-carboxylate was used in the subsequent step. Intermediate 11 - (2S,3S)-2,3-Dihydroxybutanedioic acid;2-[(2,4-difluorophenoxy)methyl]- 4-{[(2S,4S)-2-methylpiperidin-4-yl]oxy}pyrimidine L-(+)-tartrate The THF solution of tert-butyl (2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4- yl}oxy)-2-methylpiperidine-1-carboxylate (Intermediate 10) was concentrated to 4 v / w under reduced pressure. TBME (260 g) was added and the mixture was concentrated to 4 v / w under reduced pressure. TBME (260 g) was added and the mixture was concentrated to 4 v / w under reduced pressure. TBME (260 g) and water (500 g) were added and the mixture was stirred for 1 hour at 25 °C. The aqueous layer was separated and the organic layer was washed twice with water (2 x 500 g). Hydrochloric acid (246 g, 12.5 eq, 36%w / w) was added and the mixture was stirred for 3 hours at 25 °C. Aqueous sodium hydroxide (372 g) was added to adjust pH 13 at 25 °C. The aqueous layer was separated and the organic layer was washed with water (500 g). The organic layer was concentrated to 4 v / w under reduced pressure. To this solution at 50 °C, was added a solution of L-(+)-tartaric acid (31.0 g) in ethanol (74.0 g) at 50 °C. The mixture was stirred for 3 hours at 50 °C, cooled down to 0 °C over 5 hours and stirred 5 hours at 0 °C. The solids were filtered off and washed with TBME (111 g). The wet product was dried at 40 °C under reduced pressure.84.7 g (2S,3S)-2,3-Dihydroxybutanedioic acid;2-[(2,4- difluorophenoxy)methyl]-4-{[(2S,4S)-2-methylpiperidin-4-yl]oxy}pyrimidine were obtained. 2-{[(2S,4S)-4-({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid A mixture of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;methyl 2-{[(2S,4S)-4-({2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylate (100 g, 1.0 eq.; Intermediate 9), aq. potassium carbonate (707 g, 30%w / w, 10 eq.), THF (500 mL) was stirred for 2 hours at 25 °C. The organic layer was separated and concentrated to 2 v / w under reduced pressure. Methanol (125 mL), water (125 mL) and sodium hydroxide (7.78 g, 2.0 eq.) were added and the mixture was stirred for 40 hours at 15 °C. Water (500 g) was added and the mixture was concentrated to 7 v / w under reduced pressure. Acetic acid (20 g) was added over 2 hours at 5 °C to adjust to pH 5.5. The mixture was stirred for 1 hour at 5 °C. The solids were filtered off and washed with water (100 g). The wet cake, DCM (400 mL), water (100 mL), acetic acid (6.0 g) were stirred for 18 hours at 25 °C. Silica thiol (60 g) was added to the organic layer and the mixture was stirred for 2 hours at 30 °C. The solids were filtered off and the solution was concentrated to 3 v / w under reduced pressure. Methanol (200 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. Methanol (200 mL) was added and the mixture was concentrated to 3 v / w under reduced pressure. The mixture was stirred at 50 °C for 2 hours, cooled down to 20 °C over 4 hours. Water (150 mL) was added over 2 hours and the mixture was cooled down to 10 °C over 2 hours. The suspension was stirred at 10 °C for 12 hours and the solids were filtered off and washed with methanol / water (1 / 1, 200 mL). The wet product was dried at 50 °C under reduced pressure.42.25 g 2-{[(2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)- 2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid were obtained (crude). 2-{[(2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid (40 g) and methanol (658 mL) were stirred at 55 °C for 2 hours. The mixture was filtered rinsing with methanol (100 mL). The solution was cooled down to 35 °C, 2-{[(2S,4S)-4-({2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan- 2-yl]methyl}-1H-benzimidazole-6-carboxylic acid seeding crystals (0.1 g) were added and the mixture was stirred for 2 hour at 35 °C. Water (480 mL) was added over 6 hours and the mixture was cooled down to 5 °C over 4 hours and stirred for 12 hours at 5 °C. The solids were filtered off and washed with methanol / water (1 / 1, 80 mL). The wet product was dried at 45 °C under reduced pressure.32 g 2-{[(2S,4S)-4-({2-[(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2- methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid were obtained. 2-{[(2S,4S)-4-({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid (alternative route 1) A mixture of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;benzyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (348 mg, 1.00 eq., intermediate 9’), 30 w% potassium carbonate aq. solution (1.6 g,8.0 eq.), THF (2 mL) was stirred for 0.5 hour at 20 °C. The organic layer was separated and palladium on activated carbon (20mg) was added. The mixture stirred under hydrogen pressure at 50 psi and 50 °C for 18 hours. Added palladium on activated carbon (40mg) into the mixture and stirred under hydrogen pressure at 50 psi and 50 °C for another 40 hours. A mixture of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;benzyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (5.8 g, 1.00 eq., intermediate 9’), 30 w% potassium carbonate aq. solution (26.4 g, 7.9 eq.), THF (26.4 mL) was stirred for 1 hour at 20 °C. The organic layer was separated and palladium on activated carbon (330 mg) was added. The mixture stirred under hydrogen pressure at 50 psi and 50 °C for 20 hours. The mixture was filtered and rinsed with THF (6.6 mL). Added palladium on activated carbon (330 mg) into organic layer and stirred under hydrogen pressure at 50 psi and 50 °C for another 16 hours. Two reactions above were combined for work up. The mixture was filtered off and rinsed with THF (6.0 mL). H2O (9 mL) was added and the mixture was concentrated to 6.5 v under reduced pressure. MeOH (28.5 mL) was added and adjust to 10 °C for 2 hours. Acetic acid (50 mg, 0.16 eq.) was added for 0.5 hours at 10 °C to adjust to pH = 5.5. The mixture was stirred for 40 hours at 10 °C. The solids were filtered and washed with MeOH / H2O (7 mL, 2 v / 1 v). Dry the wet cake at 45 °C for 16 hours under reduced pressure. The dry cake slurried in MeOH / H2O (31 mL, 2 v / 1 v) for 16 hours at 20 °C. The solids were filtered and washed with MeOH / H2O (7 mL, 2 v / 1 v). Dry the wet cake at 45 °C for 16 hours under reduced pressure,1.8 g of 2-{[(2S,4S)-4-({2- [(2,4-difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)- oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid were obtained. 2-{[(2S,4S)-4-({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1- yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid (alternative route 2) A mixture of (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid;pentyl 2-[[(2S,4S)-4-[2-[(2,4- difluorophenoxy)methyl]pyrimidin-4-yl]oxy-2-methyl-1-piperidyl]methyl]-3-[[(2S)-oxetan-2- yl]methyl]benzimidazole-5-carboxylate (7.5 g, 1.00 eq.), 30 w% potassium carbonate aq. solution (30 g, 8.1 X), THF (30 mL) was stirred for 2 hours at 25 °C. The organic layer was separated and added silica thiol (1.2 g). The mixture stirred for 2 hours at 25 °C, filtered off and rinse with THF (7.4 mL). The mixture was concentrated to 6.5 v. Water (7.4 mL) and MeOH (7.4 mL) was added and adjust to 10 °C. NaOH (456 mg, 2.00 eq.) was added and stirred at 10 °C for 16 hours. Acetic acid (0.38 g, 1.10 eq.) was added for 0.5 hour at 10 °C to adjust to pH = 8.0. Concentrate the mixture to 6.5 v under reduced pressure. MeOH (35 mL) and acetic acid (0.27 g, 0.79 eq.) was added for 0.5 hour at 10 °C to adjust to pH = 7.5. Crystal seed of C211209005-S (20 mg) was added and stirred at 10 °C for 0.5 hour. Acetic acid (0.51 g, 1.48 eq.) was added for 0.5 hour at 10 °C to adjust to pH = 5.5. The mixture was stirred for 64 hours at 10 °C. The solids were filtered and washed with MeOH / H2O (7.4 mL, 2 v / 1 v). Dry the wet cake at 45 °C for 16 hours under reduced pressure. The dry cake slurried in MeOH / H2O (33 mL, 2 v / 1 v) for 16 hours at 20 °C. The solids were filtered and washed with MeOH / H2O (7.4 mL, 2 v / 1 v). Dry the wet cake at 45 °C for 16 hours under reduced pressure, 1.9 g of 2-{[(2S,4S)-4- ({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4-yl}oxy)-2-methylpiperidin-1-yl]methyl}-1- {[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6-carboxylic acid were obtained. Alternative routes for making 2-{[(2S,4S)-4-({2-[(2,4-Difluorophenoxy)methyl]pyrimidin-4- yl}oxy)-2-methylpiperidin-1-yl]methyl}-1-{[(2S)-oxetan-2-yl]methyl}-1H-benzimidazole-6- carboxylic acid according to Scheme 1 which have also been tested and which also provide working alternative include the following esters from the R-group: 2-ethylhexyl ester (intermediate 1’’’) and p-methoxybenzyl ester (intermediate 1’’’’).

Claims

Claims 1. A process comprising the reaction of a compound of formula (I-4)with a compound of formula (I-8)in presence of a suitable catalyst, a suitable solvent and suitable base in order to arrive at a compound of formula (I-9) or an acceptable salt thereofwherein R is alkyl, benzyl or benzyl substituted with alkoxy and wherein X is a suitable leaving group, in particular wherein R is methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec-butyl, isobutyl, n-butyl, n-pentyl, t-amyl, 2-ethylhexyl, benzyl or p-methoxybenzyl and wherein X is chloro.

2. The process according to claim 1 further comprising the following preceding step: the reaction of a compound of formula (viii) or an acceptable salt thereofwith a compound of formula (I-3)in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-4)wherein R is as defined in claim 1.

3. The process according to claim 1 further comprising the following preceding steps: (a) the reaction of a compound of formula (vii)in presence of a suitable solvent and a suitable acid to yield a compound of formula (viii) or an acceptable salt thereof(viii); and (b) the reaction of a compound of formula (viii) or an acceptable salt thereofwith a compound of formula (I-3)in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-4)wherein R is as defined in claim 1.

4. The process according to claim 2 or 3 further comprising the following preceding step: the reaction of a compound of formula (I-2)with a compound selected fromin presence of a suitable solvent and a suitable acid in order to arrive at a compound of formula (I-3)wherein R is as defined in claim 1.

5. The process according to claim 4 further comprising the following preceding steps (a) and (b), or (a’) and (b’): (a) the reaction of a compound of formula (i) or a salt thereofwith a compound of formula (ii)in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-1)(I-1); and (b) the reaction of a compound of formula (I-1)in presence of a suitable reducing agent and a suitable solvent to arrive at a compound of formula (I-2)(a’) the conversion of a compound of formula (iv)with a compound of formula (v)in presence of a suitable solvent and a suitable base to yield a compound of formula (vi)(b’) the reaction of a compound of formula (vi)with a suitable reducing agent and in presence of a suitable solvent to arrive at a compound of formula (I-2)wherein in the above process, Y is chloro or fluoro, in particular fluoro; and wherein R is as defined in claim 1.

6. The process according to claim 4 further comprising the following preceding steps: (a) the reaction of a compound of formula (i) or an acceptable salt thereofwith a compound of formula (ii)in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-1)(I-1); and (b) the reaction of a compound of formula (I-1)in presence of a suitable reducing agent and a suitable solvent to arrive at a compound of formula (I-2)wherein in the above process, Y is chloro or fluoro, in particular fluoro; and wherein R is as defined in claim 1.

7. The process according to claim 4 further comprising the following preceding steps: (a’) the conversion of a compound of formula (iv)with a compound of formula (v)in presence of a suitable solvent and a suitable base or acid to yield a compound of formula (vi)(b’) the reaction of a compound of formula (vi)with a suitable reducing agent and in presence of a suitable solvent to arrive at a compound of formula (I-2)wherein R1 is alkyl, in particular methyl; and wherein R is as defined in claim 1.

8. A process comprising the reaction of a compound of formula (I-3)with a compound of formula (I-11) or a pharmaceutically acceptable salt of a compound of formula (I-11a)in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-9) or an acceptable salt thereofwherein R is alkyl, benzyl or benzyl substituted with alkoxy, in particular wherein R is methyl, n-pentyl, t-amyl, 2-ethylhexyl, benzyl or p-methoxybenzyl.

9. The process according to any one of the preceding claims further comprising the subsequent reaction of a compound of formula (I-9) or an acceptable salt thereofwith one or more suitable deprotection reagents and in presence of a suitable solvent in order to arrive at a compound of formula (I) or a pharmaceutically acceptable salt thereofwherein R is as defined in claim 1.

0. The process according to claim 8 or 9 further comprising the precedent steps of: (a) the reaction of a compound of formula (I-8)with a compound of formula (vii)in presence of a suitable base and a suitable solvent and, optionally, a catalyst in order to arrive at a compound of formula (I-10)(I-10), and (b) the reaction of a compound of formula (I-10)(I-10) with a suitable acid and in presence of a suitable solvent to arrive at a compound of formula (I-11)L-(+)-tartrate(I-11); wherein R is as defined in claim 8.

11. A process according to any of claims 2 to 7 or claim 9 further comprising the following steps: (a) the compound of formula (I) is dissolved in a suitable solvent; (b) the mixture is filtered and the filter rinsed with a suitable solvent; (c) the solution is cooled down and / or suitable anti-sovent is added; (d) seeding crystals of the compound of formula (I) are added as powder or as suspension in a suitable solvent to the mixture; (e) the mixture is aged; (f) anti-solvent is added and the mixture cooled down; (g) the solids are filtered off and washed with a suitable solvent or solvent mixture; (h) the wet product is dried under reduced pressure.

12. A process comprising the reaction of a compound of formula (I-7)(I-7) with a suitable chlorination agent in presence of a suitable solvent and optionally a suitable base in order to arrive at a compound of formula (I-8)(I-8’).

13. A process comprising the reaction of a compound of formula (I-6)with a compound of formula (xi)in presence of a suitable base and a suitable solvent in order to arrive at a compound of formula (I-7)14. A process comprising the following steps: (a) the reaction of a compound of formula (I-5)(I-5) in presence of a suitable base and a suitable solvent to arrive at a compound of formula (I-6a)(I-6a); and (b) the subsequent reaction of the compound of formula (I-6a) with ammonium chloride to arrive at a compound of formula (I6)15. A process comprising the reaction of a compound of formula (ix)with a compound of formula (x)in presence of a suitable solvent and a suitable base in order to arrive at a compound of formula (I-5)16. A process comprising the following reactions: (a) the reaction according to claim 15; (b) the reaction according to claim 14; (c) the reaction according to claim 13; (d) the reaction according to claim 12.

17. A process according to any one of the preceding claims, wherein the acceptable salt of a compound of formula (I-9) is a salt of formula (I-9b)18. The process according to any one of the preceding claims, wherein R is alkyl, and wherein the deprotection reagent is selected from a suitable base, a suitable acid and H2+Pd / C.

19. A process according to any one of claims 1 to 18, wherein R is methyl.

20. A process according to any one of claims 1 to 18, wherein R is benzyl.

21. A process according to any one of claims 1 to 18, wherein R is n-pentyl.

22. A process according to any one of claims 1 to 18, wherein R is t-amyl.

23. A process according to any one of claims 1 to 18, wherein R is 2-ethylhexyl.

24. A process according to any one of claims 1 to 18, wherein R is p-methoxybenzyl.

25. The process according to any one of claims 1 to 18, wherein R is benzyl or benzyl substituted with alkoxy, and wherein the deprotection reagents are Pd / C and H2.

26. The process according to any one of the preceding claims wherein the catalyst is Pd2(dba)3with a BINAP or Dppp ligand, and wherein the catalyst is used in presence of toluene or 1,4-dioxane as solvent, as well as in presence of cesium carbonate as base.

27. The process according to any one of the preceding claims wherein the catalyst is GPhos Pd G3, and wherein the catalyst is used in presence of MEK, CAN, 2-MeTHF, DMC or iPrOAc as solvent, as well as in presence of K3PO4 as base.

28. The process according to any one of the preceding claims wherein the catalyst is [Pd(allyl)(Xantphos)]Cl, and wherein the catalyst is used in presence of MEK, ACN, 2- MeTHF, DMC, iPrOAc or EtOAc as solvent, as well as in presence of K3PO4 as base.

29. The process according to any one of the preceding claims, wherein the compound of formula (iii) is.

30. The process according to any one of the preceding claims, wherein the compound of formula (I-9) is.

31. The process according to any one of the preceding claims, wherein the compound of formula (viii) is.

32. The process according to any one of the preceding claims, wherein the compound of formula (i) is.

33. A compound of formula (I-6)34. A compound of formula (I-7)35. A compound of formula (I-6a)(I-6a).

36. A compound selected from.

37. A compound selected fromor an acceptable salt thereof.

38. A compound selected fromor an acceptable salt thereof.

39. A compound of formula (I-9b)40. A pharmaceutically acceptable salt of a compound of formula (I-9a)(I-9a),wherein R is methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec-butyl, isobutyl, n-butyl, n-pentyl, t-amyl, 2-ethylhexyl, benzyl or p-methoxybenzyl.

41. A compound of formula (I-11)L-(+)-tartrate(I-11).

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